Epigenetic dysregulation has emerged as an important mechanism in cancer. Alterations in epigenetic machinery have become a major focus for targeted therapies. The current report describes the discovery and biological activity of a cyclopropylamine containing inhibitor of Lysine Demethylase 1 (LSD1), GSK2879552. This small molecule is a potent, selective, orally bioavailable, mechanism-based irreversible inactivator of LSD1. A proliferation screen of cell lines representing a number of tumor types indicated that small cell lung carcinoma (SCLC) is sensitive to LSD1 inhibition. The subset of SCLC lines and primary samples that undergo growth inhibition in response to GSK2879552 exhibit DNA hypomethylation of a signature set of probes, suggesting this may be used as a predictive biomarker of activity.

The SK/IK family of small and intermediate conductance calcium-activated potassium channels contains four members, SK1, SK2, SK3 and IK1, and is important for the regulation of a variety of neuronal and non-neuronal functions. In this study we have analysed the distribution of these channels in human tissues and their cellular localisation in samples of colon and corpus cavernosum. SK1 mRNA was detected almost exclusively in neuronal tissues. SK2 mRNA distribution was restricted but more widespread than SK1, and was detected in adrenal gland, brain, prostate, bladder, liver and heart. SK3 mRNA was detected in almost every tissue examined. It was highly expressed in brain and in smooth muscle-rich tissues including the clitoris and the corpus cavernosum, and expression in the corpus cavernosum was upregulated up to 5-fold in patients undergoing sex-change operations. IK1 mRNA was present in surface-rich, secretory and inflammatory cell-rich tissues, highest in the trachea, prostate, placenta and salivary glands. In detailed immunohistochemical studies of the colon and the corpus cavernosum, SK1-like immunoreactivity was observed in the enteric neurons. SK3-like immunoreactivity was observed strongly in smooth muscle and vascular endothelium. IK1-like immunoreactivity was mainly observed in inflammatory cells and enteric neurons of the colon, but absent in corpus cavernosum. These distinctive patterns of distribution suggest that these channels are likely to have different biological functions and could be specifically targeted for a number of human diseases, such as irritable bowel syndrome, hypertension and erectile dysfunction.

: Nuclear protein in testis (NUT) carcinoma (NC) is a rare, distinctly aggressive subtype of squamous carcinoma defined by the presence of -fusion oncogenes resulting from chromosomal translocation. In most cases, the gene () is fused to bromodomain containing 4 () forming the oncogene. Here, a novel fusion partner to was discovered using next-generation sequencing and FISH from a young patient with an undifferentiated malignant round cell tumor. Interestingly, the NUT fusion identified involved ZNF592, a zinc finger containing protein, which was previously identified as a component of the BRD4-NUT complex. In BRD4-NUT-expressing NC cells, wild-type ZNF592 and other associated "Z4" complex proteins, including ZNF532 and ZMYND8, colocalize with BRD4-NUT in characteristic nuclear foci. Furthermore, ectopic expression of BRD4-NUT in a non-NC cell line induces sequestration of Z4 factors to BRD4-NUT foci. Finally, the data demonstrate the specific dependency of NC cells on Z4 modules, ZNF532 and ZNF592. IMPLICATIONS: This study establishes the oncogenic role of Z4 factors in NC, offering potential new targeted therapeutic strategies in this incurable cancer. http://mcr.aacrjournals.org/content/molcanres/16/12/1826/F1.large.jpg.

Obesity is reaching epidemic proportions in developed countries and represents a signifi cant risk factor for cardiovascular disease, diabetes, and cancer ( 1 ). Enrolment in clinical and nonclinical obesity treatment programs is unprecedented. Success in obesity treatment programs is highly variable, related in part to compliance and program characteristics (e.g., type and duration of hypocaloric diets, educational components, and/or exercise-associated energy expenditure). While it is generally well accepted that there is substantial inter-individual variability in the susceptibility to weight gain in response to overfeeding ( 2, 3 ), less well understood is the impact of biological factors on weight loss success. However, studies of monozygotic twins have shown greater inter-pair than intra-pair variation in weight loss ( 4 ), consistent with the idea that there are important genetic determinants of weight loss success. We have studied the molecular and cellular determinants of variable weight loss in highly compliant subjects in an intensively supervised and interactive hypocaloric clinical obesity treatment program at the Ottawa Hospital. We previously reported differences in muscle mitochondrial energy ineffi ciencies between program participants exhibiting high versus low weight loss success ( 5 ). Here, we extend these fi ndings by demonstrating distinct differences in skeletal muscle gene expression profi les and in structural and metabolic characteristics between individuals who Abstract Inter-individual variability in weight gain and loss under energy surfeit and defi cit conditions, respectively, are well recognized but poorly understood phenomena. We documented weight loss variability in an intensively supervised clinical weight loss program and assessed skeletal muscle gene expression and phenotypic characteristics related to variable response to a 900 kcal regimen. Matched pairs of healthy, diet-compliant, obese diet-sensitive (ODS) and dietresistant (ODR) subjects were defi ned as those in the highest and lowest quintiles for weight loss rate. Physical activity energy expenditure was minimal and comparable. Following program completion and weight stabilization, skeletal muscle biopsies were obtained. Gene expression analysis of rectus femoris and vastus lateralis indicated upregulation of genes and gene sets involved in oxidative phosphorylation and glucose and fatty acid metabolism in ODS compared with ODR. In vastus lateralis , there was a higher proportion of oxidative (type I) fi bers in ODS compared with ODR women and lean controls, fi ber hypertrophy in ODS compared with ODR women and lean controls, and lower succinate dehydrogenase in oxidative and oxidative-glycolytic fi bers in all obese compared with lean subjects. Intramuscular lipid content was generally higher in obese versus lean, and specifi cally higher in ODS vs. lean women. Altogether, our fi ndings demonstrate differences in muscle gene expression and fi ber composition related to clinical weight loss success. Abbreviations: B...